Vitamin D-binding protein: multifunctional component of blood serum

Cover Page
Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract


Vitamin D-binding protein (DBP) was discovered more than half a century ago as a polymorphic serum protein and is currently characterized by a variety of physiological properties. First of all, DBP carries the bulk of vitamin D metabolites circulating in the bloodstream, while albumin is the second most important transport protein, especially in patients with a low concentration of DBP in serum. Since it was discovered that only 1–2% of the total circulating DBP have occupied steroid binding sites, a vigorous study of other potential biological roles of DBP was initiated: actin utilization, regulation of inflammation and innate immunity mechanisms, fatty acid binding, effects on bone metabolism and participation in the tumor pathogenesis. This review focuses on the main known biological functions of DBP.


Full Text

Restricted Access

About the authors

Alexandra A. Povaliaeva

Endocrinology Research Centre

Author for correspondence.
Email: a.petrushkina@yandex.ru
ORCID iD: 0000-0002-7634-5457
SPIN-code: 1970-2811

Russian Federation, 11 Dm. Ulyanova str., 117036, Moscow

Ekaterina A. Pigarova

Endocrinology Research Centre

Email: kpigarova@gmail.com
ORCID iD: 0000-0001-6539-466X
SPIN-code: 6912-6331

Russian Federation, 11 Dm. Ulyanova str., 117036, Moscow

MD, PhD

Anastasia A. Romanova

Endocrinology Research Centre

Email: svetasvetikova1535@gmail.com
ORCID iD: 0000-0001-7112-5896
SPIN-code: 3959-5866

Russian Federation, 11 Dm. Ulyanova str., 117036, Moscow

MD

Larisa K. Dzeranova

Endocrinology Research Centre

Email: dzeranovalk@yandex.ru
ORCID iD: 0000-0002-0327-4619
SPIN-code: 2958-5555

Russian Federation, 11 Dm. Ulyanova str., 117036, Moscow

MD, PhD

Artem Y. Zhukov

Endocrinology Research Centre

Email: zhukovartem@yahoo.com
ORCID iD: 0000-0002-2729-9386
SPIN-code: 8513-7785

Russian Federation, 11 Dm. Ulyanova str., 117036, Moscow

MD

Liudmila Y. Rozhinskaya

Endocrinology Research Centre

Email: lrozhinskaya@gmail.com
ORCID iD: 0000-0001-7041-0732
SPIN-code: 5691-7775

Russian Federation, 11 Dm. Ulyanova str., 117036, Moscow

MD, PhD, Professor

References

  1. Bouillon R, van Haelen V, Rombauts W, de Moor P. The purification and characterisation of the human‐serum binding protein for the 25‐hydroxycholecalciferol (transcalciferin) identity with group‐specific component. Eur J Biochem. 1976;66(2):285–291. doi: https://doi.org/10.1111/j.1432-1033.1976.tb10518.x
  2. Imawari M, Kida K, Goodman DS. The transport of vitamin D and its 25 hydroxy metabolite in human plasma. Isolation and partial characterization of vitamin D and 25 hydroxyvitamin D binding protein. J Clin Invest. 1976;58(2):514–523. doi: https://doi.org/10.1172/JCI108495
  3. Haddad JG, Hillman L, Rojanasathit S. Human serum binding capacity and affinity for 25-hydroxyergocalciferol and 25-hydroxycholecalciferol. J Clin Endocrinol Metab. 1976;43(1):86–91. doi: https://doi.org/10.1210/jcem-43-1-86
  4. Song YH, Naumova AK, Liebhaber SA, Cooke NE. Physical and meiotic mapping of the region of human chromosome 4q11-q13 encompassing the vitamin D binding protein DBP/Gc-globulin and albumin multigene cluster. Genome Res. 1999;9(6):581–587.
  5. Bikle DD, Schwartz J. Vitamin D binding protein, total and free vitamin D levels in different physiological and pathophysiological conditions. Front Endocrinol (Lausanne). 2019;10:317. doi: https://doi.org/10.3389/fendo.2019.00317
  6. Speeckaert M, Huang G, Delanghe JR, Taes YEC. Biological and clinical aspects of the vitamin D binding protein (Gc-globulin) and its polymorphism. Clin Chim Acta. 2006;372(1–2):33–42. doi: https://doi.org/10.1016/j.cca.2006.03.011
  7. Delanghe JR, Speeckaert R, Speeckaert MM. Behind the scenes of vitamin D binding protein: More than vitamin D binding. Best Pract Res Clin Endocrinol Metab. 2015;29(5):773–786. doi: https://doi.org/10.1016/j.beem.2015.06.006
  8. Song YH, Ray K, Liebhaber SA, Cooke NE. Vitamin D-binding protein gene transcription is regulated by the relative abundance of hepatocyte nuclear factors 1α and 1β. J Biol Chem. 1998;273(43):28408–28418. doi: https://doi.org/10.1074/jbc.273.43.28408
  9. Zhang JY, Lucey AJ, Horgan R, et al. Impact of pregnancy on vitamin D status: A longitudinal study. Br J Nutr. 2014;112(7):1081–1087. doi: https://doi.org/10.1017/S0007114514001883
  10. Møller UK, Streym S, Jensen LT, et al. Increased plasma concentrations of vitamin D metabolites and vitamin D binding protein in women using hormonal contraceptives: A cross-sectional study. Nutrients. 2013;5(9):3470–3480. doi: https://doi.org/10.3390/nu5093470
  11. Nykjaer A, Dragun D, Walther D, et al. An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell. 1999;96(4):507–515. doi: https://doi.org/10.1016/s0092-8674(00)80655-8
  12. Guha C, Osawa M, Werner PA, et al. Regulation of human Gc (vitamin D-binding) protein levels: Hormonal and cytokine control of gene expression in vitro. Hepatology. 1995;21(6):1675–1681.
  13. Wang X, Shapses SA, Al-Hraishawi H. Free and bioavailable 25-hydroxyvitamin D levels in patients with primary hyperparathyroidism. Endocr Pract. 2017;23(1):66–71. doi: https://doi.org/10.4158/EP161434.OR
  14. Thrailkill KM, Fowlkes JL. The role of vitamin D in the metabolic homeostasis of diabetic bone. Clin Rev Bone Min Metab. 2014;11(1):28–37. doi: https://doi.org/10.1007/s12018-012-9127-9
  15. Anderson RL, Ternes SB, Strand KA, Rowling MJ. Vitamin D homeostasis is compromised due to increased urinary excretion of the 25-hydroxycholecalciferol-vitamin D-binding protein complex in the Zucker diabetic fatty rat. Am J Physiol Endocrinol Metab. 2010;299(6):959–967. doi: https://doi.org/10.1152/ajpendo.00218.2010
  16. Altinova AE, Ozkan C, Akturk M, et al. Vitamin D-binding protein and free vitamin D concentrations in acromegaly. Endocrine. 2016;52(2):374–379. doi: https://doi.org/10.1007/s12020-015-0789-1
  17. Björkhem-Bergman L, Torefalk E, Ekström L, Bergman Pl. Vitamin D binding protein is not affected by high-dose vitamin D supplementation: A post hoc analysis of a randomised, placebo-controlled study. BMC Res Notes. 2018;11(1):619. doi: https://doi.org/10.1186/s13104-018-3725-7
  18. Bouillon R, Schuit F, Antonio L, Rastinejad F. Vitamin D binding protein: a historic overview. Front Endocrinol (Lausanne). 2020;10:910. doi: https://doi.org/10.3389/fendo.2019.00910
  19. Bouillon R. Genetic and racial differences in the vitamin D Endocrine System. Endocrinol. Metab Clin North Am. 2017;46(4):1119–1135. doi: https://doi.org/10.1016/j.ecl.2017.07.014
  20. Haughton MA, Mason RS. Immunonephelometric assay of vitamin D-binding protein. Clin Chem. 1992;38(9):1796–1801.
  21. Jørgensen CS, Christiansen M, Nørgaard-Pedersen E, et al. Gc globulin (vitamin D-binding protein) levels: An inhibition ELISA assay for determination of the total concentration of Gc globulin in plasma and serum. Scand J Clin Lab Invest. 2004;64(2):157–166. doi: https://doi.org/10.1080/00365510410001149
  22. Henderson CM, Lutsey PL, Misialek JR, et al. Measurement by a novel LC-MS/MS methodology reveals similar serum concentrations of vitamin D binding protein in blacks and whites. Clin Chem. 2017;62(1):179–187. doi: https://doi.org/10.1373/clinchem.2015.244541
  23. Kilpatrick LE, Phinney K.W. Quantification of total vitamin-D-binding protein and the glycosylated isoforms by liquid chromatography − isotope dilution mass spectrometry. J Proteome Res. 2017;16(11):4185–4195. doi: https://doi.org/10.1021/acs.jproteome.7b00560
  24. Cooke NE, Haddad JG. Vitamin D binding protein (GC-globulin). Endocr. Rev. 1989;10(3):294–307. doi: https://doi.org/10.1210/edrv-10-3-294
  25. Duchow EG, Cooke NE, Seeman J, et al. Vitamin D binding protein is required to utilize skin-generated vitamin D. Proc Natl Acad Sci USA. 2019;116(49):24527–24532. doi: https://doi.org/10.1073/pnas.1915442116
  26. Bikle DD, Gee E, Halloran B, et al. Assessment of the free fraction of 25-hydroxyvitamin. J Clin Endocrinol Metab. 1986;63(4):954–959. doi: https://doi.org/10.1210/jcem-63-4-954
  27. Heureux N, Lindhout E, Swinkels L. A direct assay for measuring free 25-hydroxyvitamin D. J AOAC Int. 2017;100(5):1318–1322. doi: https://doi.org/10.5740/jaoacint.17-0084
  28. Nielson CM, Jones KS, Chun RF, et al. Free 25-hydroxyvitamin D: impact of vitamin D binding protein assays on racial-genotypic associations. J Clin Endocrinol Metab. 2016;101(5):2226–2234. doi: https://doi.org/10.1210/jc.2016-1104
  29. Nielson CM, Jones KS, Bouillon R, et al. Role of assay type in determining free 25-hydroxyvitamin D levels in diverse populations. N Engl J Med. 2016;374(17):1695–1696. doi: https://doi.org/10.1056/NEJMc1513502
  30. Bouillon R, van Assche FA, van Baelen H, et al. Influence of the vitamin D-binding protein on the serum concentration of 1,25-dihydroxyvitamin D3. Significance of the free 1,25-dihydroxyvitamin D3 concentration. J Clin Invest. 1981;67(3):589–596. doi: https://doi.org/10.1172/JCI110072
  31. Chun RF, Lauridzen AL, Suon L, et al. Vitamin D-binding protein directs monocyte responses to 25-hydroxy- and 1,25-dihydroxyvitamin D. J Clin Endocrinol Metab. 2010;95(7):3368–3376. doi: https://doi.org/10.1210/jc.2010-0195
  32. Zella LA, Shevde NK, Hollis BW, et al. Vitamin D-binding protein influences total circulating levels of 1,25-dihydroxyvitamin D3 but does not directly modulate the bioactive levels of the hormone in vivo. Endocrinology. 2008;149(7):3656–3667. doi: https://doi.org/10.1210/en.2008-0042
  33. Chun RF, Peercy BE, Orwol ES, et al. Vitamin D and DBP: The free hormone hypothesis revisited. J Steroid Biochem Mol Biol. 2014;144 (Pt A):132–137. doi: https://doi.org/10.1016/j.jsbmb.2013.09.012
  34. Nykjaer A, Fyfe JC, Kozyraki R, et al. Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D3. Proc. Natl. Acad Sci U S A. 2001;98(24):13895–13900. doi: https://doi.org/10.1073/pnas.241516998
  35. Leheste JR, Melsen F, Wellner М, et al. Hypocalcemia and osteopathy in mice with kidney-specific megalin gene defect. FASEB J. 2003;17(2):247–249. doi: https://doi.org/10.1096/fj.02-0578fje
  36. Safadi FF, Thornton P, Magiera H, et al. Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein. J Clin Invest. 1999;103(2):239–251. doi: https://doi.org/10.1172/JCI5244
  37. Kongsbak M, Von Essen MR, Levring TB, et al. Vitamin D-binding protein controls T cell responses to vitamin D. BMC Immunol. 2014;15:35. doi: https://doi.org/10.1186/s12865-014-0035-2
  38. Henderson CM, Fink SL, Bassyouni H, et al. Vitamin D-binding protein deficiency and homozygous deletion of the GC gene. N Engl J Med. 2019;380(12):1150–1157. doi: https://doi.org/10.1056/NEJMoa1807841
  39. Dueland S, Nenseter MS, Drevon C. Uptake and degradation of filamentous actin and vitamin D-binding protein in the rat. Biochem J. 1991;274(1):237–241. doi: https://doi.org/10.1042/bj2740237
  40. Dahl B, Schiødt FV, Gehrchen PM, et al. Gc-globulin is an acute phase reactant and an indicator of muscle injury after spinal surgery. Inflamm Res. 2001;50(1):39–43.
  41. Horváth-szalai Z, Kustán P, Szirmay B, et al. Predictive value of serum gelsolin and Gc globulin in sepsis — a pilot study. Clin Chem Lab Med. 2018;56(8):1373–1382. doi: https://doi.org/10.1515/cclm-2017-0782
  42. Gressner OA, Gao C, Siluschek M, et al. Inverse association between serum concentrations of actin-free vitamin D-binding protein and the histopathological extent of fibrogenic liver disease or hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 2009;21(9):990–995. doi: https://doi.org/10.1097/MEG.0b013e3283293769
  43. Lind SE, Smith DB, Janmey PA, Stossel TP. Depression of gelsolin levels and detection of gelsolin-actin complexes in plasma of patients with acute lung injury. Am Rev Respir Dis. 1988;138(2):429–434. doi: https://doi.org/10.1164/ajrccm/138.2.429
  44. Tannetta DS, Redman CW, Sargent IL. Investigation of the actin scavenging system in pre-eclampsia. Eur J Obstet Gynecol Reprod Biol. 2014;172(100):32–35. doi: https://doi.org/10.1016/j.ejogrb.2013.10.022
  45. Behrouz GF, Farzaneh GS, Leila J, et al. Presence of auto-antibody against two placental proteins, annexin A1 and vitamin D binding protein, in sera of women with pre-eclampsia. J Reprod Immunol. 2013;99(1–2):10–16. doi: https://doi.org/10.1016/j.jri.2013.04.007
  46. Dinsdale RJ, Hazeldine J, Al Tarrah K, et al. Dysregulation of the actin scavenging system and inhibition of DNase activity following severe thermal injury. Br J Surg. 2020;107(4):391–401. doi: https://doi.org/10.1002/bjs.11310
  47. Madden K, Feldman HA, Chun RF, et al. Critically ill children have low vitamin D binding protein, influencing bioavailability of vitamin D. Ann Am Thorac Soc. 2015;12(11):1654–1661. doi: https://doi.org/10.1513/AnnalsATS.201503-160OC
  48. Waldron JL, Ashby HL, Cornes MP, et al. Vitamin D: A negative acute phase reactant. J Clin Pathol. 2013;66(7):620–622. doi: https://doi.org/10.1136/jclinpath-2012-201301
  49. Wang HH, Cheng BL, Chen QX, et al. Time course of plasma gelsolin concentrations during severe sepsis in critically ill surgical patients. Crit Care. 2008;12(4):R106. doi: https://doi.org/10.1186/cc6988
  50. Dahl B, Schiødt FV, Rudolph S, et al. Trauma stimulates the synthesis of Gc-globulin. Intensive Care Med. 2001;27(2):394–399. doi: https://doi.org/10.1007/s001340000837
  51. Schiødt FV, Ott P, Bondesen S, Tygstrup N. Reduced serum Gc-globulin concentrations in patients with fulminant hepatic failure: association with multiple organ failure. Crit Care Med. 1997Aug;25(8):1366–1370. doi: https://doi.org/10.1097/00003246-199708000-00025
  52. Leaf DE, Waikar SS, Wolf M, et al. Dysregulated mineral metabolism in patients with acute kidney injury and risk of adverse outcomes. Clin Endocrinol (Oxf). 2013;79(4):491–498. doi: https://doi.org/10.1111/cen.12172
  53. Swamy N, Ray R. Fatty acid-binding site environments of serum vitamin D-binding protein and albumin are different. Bioorg Chem. 2008;36(3):165–168. doi: https://doi.org/10.1016/j.bioorg.2008.02.002
  54. Ena JM, Esteban C, Perez MD, et al. Fatty acids bound to vitamin D-binding protein (DBP) from human and bovine sera. Biochem Int. 1989;19(1):1–7.
  55. Bouillon R, Xiang DZ, Convents R, van Baelen H. Polyunsaturated fatty acids decrease the apparent affinity of vitamin D metabolites for human vitamin D-binding protein. J Steroid Biochem Mol Biol. 1992;42(8):855–861. doi: https://doi.org/10.1016/0960-0760(92)90094-y
  56. Ravnsborg T, Olsen DT, Thysen AH, et al. The glycosylation and characterization of the candidate Gc macrophage activating factor. Biochim Biophys Acta. 2010;1804(4):909–917. doi: https://doi.org/10.1016/j.bbapap.2009.12.022
  57. Borges CR, Rehder DS. Glycan structure of Gc protein-derived macrophage activating factor as revealed by mass spectrometry. Arch Biochem Biophys. 2016;606:167–179. doi: https://doi.org/10.1016/j.abb.2016.08.006
  58. Mohamad SB, Nagasawa H, Uto Y, Hori H. Tumor cell alpha-N-acetylgalactosaminidase activity and its involvement in GcMAF-related macrophage activation. Comp Biochem Physiol A Mol Integr Physiol. 2002;132(1):1–8. doi: https://doi.org/10.1016/s1095-6433(01)00522-0
  59. Schneider GB, Grecco KJ, Safadi FF, Popoff SN. The anabolic effects of vitamin D-binding protein-macrophage activating factor (DBP-MAF) and a novel small peptide on bone. Crit Rev Eukaryot Gene Expr. 2003;13(2–4):277–284. doi: https://doi.org/10.1615/critreveukaryotgeneexpr.v13.i24.190
  60. Saburi E, Saburi A, Ghanei M. Promising role for Gc-MAF in cancer immunotherapy: From bench to bedside. Casp J Intern Med. 2017;8(4):228–238. doi: https://doi.org/10.22088/cjim.8.4.228
  61. Yamamoto N, Ushijima N, Koga Y. Immunotherapy of HIV-Infected patients with gc protein-derived macrophage activating factor (GcMAF). J Med Virol. 2009;81(1):16–26. doi: https://doi.org/10.1002/jmv.21376
  62. Останин А.А., Кирикович С.С., Долгова Е.В., и др. Тернистый путь макрофаг-активирующего фактора (GcMAF): от открытия к клинической практике // Вавиловский журнал генетики и селекции. — 2019. — Т. 23. — № 5. — С. 624–631. [Ostanin AA, Kirikovich SS, Dolgova EV, et al. A thorny pathway of macrophage activating factor (GcMAF): from bench to bedside. Vavilovskii Zhurnal Genetiki i Selektsii. 2019;23(5):624–631. (In Russ.)] doi: https://doi.org/10.18699/VJ19.535
  63. Yamamoto N, Naraparaju VR, Urade M. Prognostic utility of serum α-N-acetylgalactosaminidase and immunosuppression resulted from deglycosylation of serum Gc protein in oral cancer patients. Cancer Res. 1997;57(2):295–299.
  64. Yamamoto N, Naraparaju VR. Vitamin D3-binding protein as a precursor for macrophage activating factor in the inflammation-primed macrophage activation cascade in rats. Cell Immunol. 1996;170(2):161–167. doi: https://doi.org/10.1006/cimm.1996.0148
  65. Safety Study of EF-022 (Modified vitamin D binding protein macrophage activator) in subjects with advanced solid tumors [Internet]. ClinicalTrials.gov: National Library of Medicine (US) [updated 2017 Jun 20; cited 2020 Jul 11]. Available from: https://clinicaltrials.gov/ct2/show/NCT02052492?term=NCT02052492&draw=2&rank=1
  66. McVoy LA, Kew RR. CD44 and annexin A2 mediate the C5a chemotactic cofactor function of the vitamin D binding protein. J Immunol. 2005;175(7):4754–4760. doi: https://doi.org/10.4049/jimmunol.175.7.4754
  67. Trujillo G, Zhang J, Habiel DM, et al. Cofactor regulation of C5a chemotactic activity in physiological fluids. Requirement for the vitamin D binding protein, thrombospondin-1 and its receptors. Mol Immunol. 2011;49(3):495–503. doi: https://doi.org/10.1016/j.molimm.2011.09.024
  68. Binder R, Kress A, Kan G, et al. Neutrophil priming by cytokines and vitamin D binding protein (Gc-globulin): Impact on C5a-mediated chemotaxis, degranulation and respiratory burst. Mol Immunol. 1999;36(13–14):885–892. doi: https://doi.org/10.1016/s0161-5890(99)00110-8
  69. Trujillo G, Habiel DM, Ge L, et al. Neutrophil recruitment to the lung in both C5a- and CXCL1-induced alveolitis is impaired in vitamin D-binding protein deficient-mice. J Immunol. 2013;191(2):848–856. doi: https://doi.org/10.4049/jimmunol.1202941
  70. Shah AB, DiMartino SJ, Trujillo G, Kew RR. Selective inhibition of the C5a chemotactic cofactor function of the vitamin D binding protein by 1,25(OH)2 Vitamin D3. Mol Immunol. 2006;43(8):1109–1115. doi: https://doi.org/10.1016/j.molimm.2005.07.023
  71. Raymond MA, Désormeaux A, Labelle A, et al. Endothelial stress induces the release of vitamin D-binding protein, a novel growth factor. Biochem Biophys Res Commun. 2005;338(3):1374–1382. doi: https://doi.org/10.1016/j.bbrc.2005.10.105.

Supplementary files

Supplementary Files Action
1.
Рис. 1. Различия в структуре самых распространенных изоформ DBP и образование DBP-MAF. Аллель 1F кодирует последовательность между аминокислотами 432 и 436 как DATPT, аллель 1S — как EATPT, аллель 2 — как DATPK. Две из трех указанных изоформ (DBP1F и DBP1S) могут быть гликозилированы по треонину в 420-й позиции трисахаридом. Частичное дегликозилирование с удалением галактозы и сиаловой кислоты за счет последовательного действия сиалидазы и β-галактозидазы Т- и В-клеток приводит к образованию из DBP фактора активации макрофагов (DBP-MAF).

Download (132KB) Indexing metadata

Statistics

Views

Abstract - 97

PDF (Russian) - 0

Cited-By


Article Metrics

Metrics Loading ...

PlumX

Dimensions



Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies